9.0 RISKS AND POTENTIAL BENEFITS 
9.1 Risks Related to the AAV-CFTR vector 
The risks associated with the use of the AAV-CFTR vector are relatively unknown. The 
normal AAV virus is not associated with any diseases or illnesses in humans. 
9.1.1 Inflammatory Reactions 
It is possible that the vector or vector preparation could trigger acute bronchospasm upon 
administration. Application of vector could result in inflammation of the nasal mucosa or 
bronchial lining, resulting in pain, bleeding, fever, bronchoconstriction, or scarring; these 
events could predispose the subject to secondary bacterial or viral pneumonia. The 
administration of vector in a careful dose escalation fashion and anatomical placement in 
one nostril and/or one lung lobe potentially limits these effects. 
9.1.2 Immune Reactions 
It is possible that the vector particles or expression of the normal CFTR gene could lead to 
a humoral or cellular immune response directed against cells modified by the vector. This 
could lead to destruction of the modified cells, and could affect the response to subsequent 
administration of AAV and/or CFTR vectors. 
9.1.3 Virus Replication 
The AAV-CFTR vector is completely replication defective and cannot produce any AAV 
proteins. The vector could replicate if a modified cell carrying this vector were to be 
infected simultaneously with wild type AAV and adenovirus. In the unlikely event that this 
were to occur, it is probable that preferential packaging of wild type AAV would out- 
compete packaging of vector. 
9.1.4 Insertional Mutagenesis 
AAV vectors are capable of integration into the host chromosomal DNA, although the 
distribution of integration sites in normal non-dividing respiratory epithelium is at the 
present unknown. It is possible that integration could result in overexpression of 
oncogenes or disruption of tumor suppressor genes, potentially enhancing the risk of 
malignant transformation. Enhancement of oncogene expression is unlikely due to the lack 
of a strong promoter in the tgAAVCF vector. Disruption of tumor suppressor genes is a 
possibility, but both alleles would need to be inactivated for phenotypic changes to occur. 
The risk of tumorigenesis as a direct result of vector administration appears to be of low 
probability; tumorigenesis mediated by AAV has never been reported. 
9.1.5 Environmental Risks 
It is possible that the AAV-CFTR vector could be transmitted to another person. As 
described in 9.1.3, this appears to be an unlikely possibility. However, the potential for 
inteipatient transmission will be minimized by (1) screening patients for active adenovirus 
and AAV infections prior to vector administration; (2) maintaining respiratory isolation 
throughout the active phase of the study; and (3) using sensitive culture methods to detect 
the presence of infectious AAV-CFTR virus following vector administration. 
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